The kinetics of T lymphocytes underlie the lymphopenia that defines AIDS. Most kinetic models of HIV immunopathogenesis have been relatively simple, focusing on the presence or absence of virus and the global "turnover" rate (high or low) of T cells. Our contention has been that the immunobiology of the host is more complex, but is equally important to consider. In particular, the sources of T cells produced (thymus, extra-thymic pathways) and their kinetic fates (naive or memory-effector [m/e]; long-lived or short-lived) are key to any understanding of the development of immune deficiency. In the first phase of this project, we developed new techniques for measuring the kinetic behavior of proliferating T cell subpopulations in humans, including HIV-1-infected subjects. This work, performed in collaboration with the McCune laboratory, suggested that the production of short-lived m/e phenotype T ceils is well maintained in HIV/AIDS but the capacity to produce long-lived CD4+ and CD8+ T cells is deficient. Correlations between thymic function and T cell kinetics were also described. The goals of the present proposal are to take advantage of recent technical developments to investigate the hypothesis that maintenance of a functional T cell immune system in the face of HIV-1 infection depends critically on the sources of T cells produced and their capacity for long lifespan, which in turn depends upon the maintenance of thymic function. T cell kinetics will be measured by use of the long-term heavy water (2H20) labeling/die-away/fluorescence-activated cell sorting technique that we recently developed. The specific aims are (1) to measure in detail the proliferation rate and lifespan of naive phenotype 1"cells, including distinction between peripheral expansion, transitional proliferation and thymopoiesis, and to compare to independent measures of thymic function (thymic mass, T-cell receptor excision circle content, V beta repertoire, and naive T-cell counts) in healthy controls (n=12) HIV-1-infected subjects (untreated [n=12]; effective virologic suppression [n=12]; and incomplete suppression with protease inhibitor-resistant viremia [n=12]); (2) to establish the relationship between thymic function and the capacity to produce long-lived m/e-phenotype (i.e. true memory) T cells, in these clinical settings; (3) to determine the effects of recombinant growth hormone treatment on production of naive and m/e-phenotype T cells and indices of thymic function in HIV-1 infected patients with virologic suppression and low thymic mass (n=12); and 4) to establish the role of thymic function in T cell homeostasis in mice with chronic immune activation (TCR transgenic D011.10 mice stimulated with cognate OVA 323-329 peptide). These studies are part of an IRPG with Dr. J.M McCune. In summary, advances in technology now make it possible to directly address hypotheses concerning the role of thymic function in HIV-1 pathogenesis and the kinetic consequences of HIV-1 infection and therapies.